Chemokines have been recognized as a critical component of basal leukocyte trafficking essential for normal immune surveillance and response, as well as for several other functions in hematopoiesis, angiogenesis, control of viral infection, and T cell differentiation (Baggiolini et al., Ann. Rev. Immunol. 15:675 (1997); Zou et al., Nature 393:595 (1998); Tachibana et al., Nature 393:591 (1998)). This diverse array of biological activities, including mediation of a range of pro-inflammatory effects on leukocytes, such as triggering of chemotaxis, degranulation, synthesis of lipid mediators, and integrin activation, together with their critical role in the initiation and maintenance of inflammatory diseases, have made chemokines and chemokine receptors an attractive new set of therapeutic targets.
Chemokine receptor 4 (CCR4) was identified by Power et al. (J. Biol. Chem. 270:19495-19500 (1995); Genbank accession number X85740) and Meyer et al. (J. Biol. Chem. 271(24):14445-14451 (1996); Genbank accession number X94151). CCR4 is a seven-transmembrane G-protein coupled receptor and selectively expressed on Th2 cells and regulatory T cells (D'Ambrosio, et al. J. Immunol. 161:5111-5115 (1998)). CCR4 expression on normal cells such as Th2 cells can be partly regulated by the ligand, especially macrophage-derived chemokine (MDC) (Mariani et al., Eur. J. Immunol. 34:231-240 (2004)), while the regulation by the ligands on cancer cells is not yet understood. It has been shown that anti-CCR4 monoclonal antibody selectively depletes effector-type FoxP3+CD4+ regulatory T cells, evoking antitumor immune responses in humans (Sugiyama et al., Proc. Nat. Acad. Sci. 110(44):17945-17950 (2003)).
KW-0761 (mogamulizumab or POTELIGEO™) is approved in Japan for relapsed or refractory CCR4-positive adult T-cell leukemia/lymphoma and relapsed or refractory CCR4-positive peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma (CTCL). KW-0761 is a humanized monoclonal antibody of the immunoglobulin G, subclass 1 (IgG1) kappa isotype that targets CCR4 expressing cells and has shown an ability to deplete T-lymphocytes expressing CCR4 via ADCC. KW-0761 has enhanced ADCC activity due to defucosylation from the complex-type oligosaccharide at the constant (Fc) region. (Ishii et al., Clinical Cancer Research 16: 1520-31 (2010); Shitara et al., Human CDR-grafted antibody and antibody fragment thereof, U.S. Pat. No. 7,504,104; U.S. Pat. No. 8,491,901).
4-1BB (CD137 and TNFRSF9), which was first identified as an inducible costimulatory receptor expressed on activated T cells, is a membrane spanning glycoprotein of the Tumor Necrosis Factor (TNF) receptor superfamily. Current understanding of 4-1BB indicates that expression is generally activation dependent and encompasses a broad subset of immune cells including activated NK and NKT cells, regulatory T cells, dendritic cells (DC) including follicular DC, stimulated mast cells, differentiating myeloid cells, monocytes, neutrophils, eosinophils (Wang et al., Immunol Rev. 229(1):192-215 (2009)), and activated B cells (Zhang et al., J Immunol. 184(2):787-795 (2010)). 4-1BB expression has also been demonstrated on tumor vasculature (Broll K et al., Am J Clin Pathol. 115(4):543-549 (2001); Seaman et al., Cancer Cell 11(6):539-554 (2007)) and atherosclerotic endothelium (Olofsson et al., Circulation 117(10):1292 1301 (2008)). The ligand that stimulates 4-1BB (4-1BBL) is expressed on activated antigen-presenting cells (APCs), myeloid progenitor cells and hematopoeitic stem cells.
Interaction of 4-1BB on activated normal human B cells with its ligand at the time of B cell receptor engagement stimulates proliferation and enhances survival (Zhang et al., J Immunol. 184(2):787-795 (2010)). The potential impact of 4-1BB engagement in B cell lymphoma has been investigated in two published studies. Evaluation of several types of human primary NHL samples indicated that 4-1BB was expressed predominantly on infiltrating T cells rather than the lymphoma cells (Houot et al., Blood 114(16):3431-3438 (2009)). The addition of 4-1BB agonists to in vitro cultures of B lymphoma cells with rituximab and NK cells resulted in increased lymphoma killing (Kohrt et al., Blood 117(8):2423-2432 (2011)). In addition, B cell immunophenotyping was performed in two experiments using PF-05082566 (anti-4-1BB agonist monoclonal antibody) in cynomolgus monkeys with doses from 0.001-100 mg/kg; in these experiments peripheral blood B cell numbers were either unchanged or decreased.
4-1BB is undetectable on the surface of naive T cells but expression increases upon activation. Upon 4-1BB activation, TRAF-1 and TRAF-2, which are pro-survival members of the TNFR-associated factor (TRAF) family, are recruited to the 4-1BB cytoplasmic tail, resulting in downstream activation of NFκB and the Mitogen Activated Protein (MAP) Kinase cascade including ERK, JNK, and p38 MAP kinases. NFkB activation leads to upregulation of Bfl-1 and Bcl-XL, pro-survival members of the Bcl-2 family. The pro-apoptotic protein Bim is downregulated in a TRAF-1 and ERK dependent manner (Sabbagh et al., J Immunol. 180(12):8093-8101 (2008)).
Reports have shown that 4-1BB agonist mAbs increase costimulatory molecule expression and markedly enhance cytolytic T lymphocyte responses, resulting in anti-tumor efficacy in various models. 4-1BB agonist mAbs have demonstrated efficacy in prophylactic and therapeutic settings for both monotherapy and combination therapy and have established durable anti-tumor protective T cell memory responses (Lynch et al., Immunol Rev. 222:277-286 (2008)). 4-1BB agonists also inhibit autoimmune reactions in a variety of autoimmunity models (Vinay et al., J Mol Med 84(9):726-736 (2006)).